World Health Organization

Prequalification of Medicines
Manufacturers meeting April 2011
Dr Andr van Zyl
Head of Inspections

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Dr AJ van Zyl | April 2011

vanzyla@who.int

WHO GMP
In this presentation:
z Background and Introduction GMP
WHO PIC/S EU - USA

z Manufacturer survey 2010

z Discussion

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Dr AJ van Zyl | April 2011

GMPs
WHO GMP

EU and PIC/SGMP

z First WHO GMP published in 1967

z Directives published in 1989

z Revised on an ongoing basis

z Other "local" GMP existed well before

this date

Revisions circulated for comment,

informal consultations
Expert Committee published in
TRS

z PIC formed in 1970, PIC/S formed in

1995

z Main principles

z EU and PIC/S GMP similar

z "Supplementary" guidelines

z PIC/S GMP based on WHO GMP

z Used in over 100 countries

z 39 Participating authorities

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Dr AJ van Zyl | April 2011

WHO and PIC/S GMP

WHO GMP

PIC/S GMP

Main principles

Main principles

Sterile product manufacture

Manufacture of sterile medicinal products

Heating, Ventilation and Air Conditioning (HVAC) systems

Manufacture of biological medicinal products for human use

Manufacture of radiopharmaceuticals

Water for pharmaceutical use

Manufacture of veterinary medicinal products other than immunologicals

Quality Control laboratories

Manufacture of immunological veterinary medical products

Radiopharmaceuticals

Manufacture of medicinal gases

Good Storage Practices (GSP)

Manufacture of herbal medicinal products

Good Distribution Practices (GDP)

Sampling of starting and packaging materials

Manufacture of liquids, creams and ointments

Good Trade and Distribution Practices (GTDP)

Manufacture of pressurised metered dose aerosol preparations for inhalation

Sampling

Computerised systems

Herbal products

Use of ionising radiation in the manufacture of medicinal products

Hazard Analysis and Critical Control Point (HACCP)

Manufacture of investigational medicinal products

Reference standards

Manufacture of products derived from human blood or human plasma

Qualification and validation

Validation

Parametric release

GMP for APIs

GMP Guide for active pharmaceutical ingredients

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Dr AJ van Zyl | April 2011

Examples
WHO

PIC/S

16.17 Means should be instituted of

indicating failures of equipment or of
services (e.g. water, gas) to equipment.
Defective equipment should be withdrawn
from use until the defect has been rectified.
After use, production equipment should be
cleaned without delay according to detailed
written procedures and stored under clean
and dry conditions in a separate area or in
a manner that will prevent contamination.

16.18 Time limits for storage of equipment

after cleaning and before use should be
stated and based on data.

16.19 Containers for filling should be

cleaned before filling. Attention should be
given to avoiding and removing any
contaminants such as glass fragments and
metal particles.

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Dr AJ van Zyl | April 2011

Examples
WHO

PIC/S

16.23

3.41

Measuring, weighing, recording, and control

equipment and instruments should be serviced and
calibrated at prespecified intervals and records
maintained.

Measuring, weighing, recording and control equipment

should be calibrated and checked at defined intervals by
appropriate methods. Adequate records of such tests
should be maintained.

To ensure satisfactory functioning, instruments

should be checked daily or prior to use for performing
analytical tests. The date of calibration and servicing
and the date when recalibration is due should be
clearly indicated, preferably on a label attached to the
instrument.

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Dr AJ van Zyl | April 2011

Survey
z

Manufacturer's survey done in 2010 contracted party

Limited to identified manufacturers with prequalified products - majority in India

Online questionnaire divided into four sections:

1.
2.
3.
4.

Section 2 (Design) is custom to the PQP developed as a result of a process review with the
WHO PQP Staff and a series of interviews with pharmaceutical manufacturers

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Two multi-item questions for both assessments and inspections

Two separate multi-item questions each for assessments and inspections respectively

Section 3 (Delivery) is a widely-applied scale of service quality, SERVQUAL (Parasuraman,

Zeithaml, Berry)1, developed in the 1980s; refined and applied over past 25 years

Previous PQP Experience

PQP Service Design (process)
PQP Service Delivery (people)
Other Aspects of the PQP

Five separate multi-item questions each for assessments and inspections respectively

Section 4 is also custom to the PQP and includes advocacy, training and compliance aspects
of the PQP

Dr AJ van Zyl | April 2011

Survey
z A list of potential survey participants was compiled by the WHO PQP Staff using
internal records
Regulatory Affairs Professionals (assessment of product dossiers)
Quality Assurance Professionals (on-site inspections)
Inclusion criterion: participation in the PQP of Medicines 2006 - 2010

z Contact list represents known population of manufacturer PQP participants: 75

original contacts; later revised to 62 (30 regulatory, 32 QA)
z Sampling plan: census all contacts received an e-mail invitation
z All invitations sent by e-mail with two reminders; some follow up telephone
reminders
z 41 completed surveys received by 20 July (66% response rate)
Surveys oriented toward assessment of product dossiers: 18
Surveys oriented toward on-site inspections: 23

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Dr AJ van Zyl | April 2011

Survey
7.0
6.4*
6.0

6.0

6.1
6.0

6.1*
5.8

5.0*

5.0*

5.3

Average Rating

5.3*
5.0

6.1*

6.1*
5.8
5.0*

4.8*

4.0

3.0

2.0

1.0

Providing clear
Providing applicants /
Providing a site
Providing direct access Providing an efficient
explanations of good
manufacturers with
inspection plan that
to inspectors to
process to resolve
manufacturing practice timely announcements
includes all the
address technical
issues and questions
deficiencies observed
of inspections
information needed to
questions or
raised during the
during inspection of a
prepare for an
deficiencies
inspection of
manufacturing site
inspection
manufacturing sites

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Dr AJ van Zyl | April 2011

Survey

Question

Item

Comment

Q7C.1

Providing clear explanations of good manufacturing practice deficiencies

observed during inspection of a manufacturing site

Review of pre-qualification dossiers and subsequent responses should be addressed on a fast tract to help the FP
manufacturer's.

Q7C.1

Providing clear explanations of good manufacturing practice deficiencies

observed during inspection of a manufacturing site

Inspection process is fair and upto the mark.

Q7C.1

The deficiencies must be evaluated with risk to product , patient and process

Q7D.1

Providing clear explanations of good manufacturing practice deficiencies

observed during inspection of a manufacturing site
Providing clear interpretation of GMP requirements

Q7D.1

Providing clear interpretation of GMP requirements

Q7D.1

Providing clear interpretation of GMP requirements

Q7D.2

Providing an efficient process to resolve issues and questions raised

following the inspection of manufacturing sites

Q7D.3
Q7D.4

Providing an inspection process that makes efficient use of manufacturers

time
The clarity of questions asked during the inspection process

1. Thorough communication with the manufacturers; 2. Interpretation and application of GMP terms.

Q7D.4

The clarity of questions asked during the inspection process

On new aspects / updation in expectation of regulatory, site team must be briefed

Q7D.4

The clarity of questions asked during the inspection process

Q7D.4

The clarity of questions asked during the inspection process

Q7D.5

Including inspectors from your country or region on the inspection team

We are simultaneously working for compliance with all regulatory authorities. Sometimes we come across discrepancies in
standards of different authorities. At such times we expect guidance from WHO on which standards should be followed so that
we have harmonised standards for all global regulatory authorities. For example guidance on tablets formulations by Dr. Van Zyl
is available, we expect similar guidance for other formulations.
Some of the questions could be more specific and practical. If the manufacturer's response is not satisfactory, the inspector
should say so on site and, if possible/appropriate, provide some further instructions.
Outof 4 WHO inspcetions, only one tine inspector from our country participated in the audit only for an hour. That's why rated 3.
Need to have firm commitment from Minsitry of Health for auditing facilities along with WHO Geneva auditors. A report from
WHO auditors to ministry of health regarding prsence of local inspector and on his performance may improve this.

Q7D.5

Including inspectors from your country or region on the inspection team

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Dr AJ van Zyl | April 2011

At least once in 6 months followup audit by QA professional of other organization. example: Mylan labs QA head audit
aurobindo facily or Aurobindo QA head audit Mylan facilty
If more training programs for pharmaceutical manufacturers could be organized, it would be much better.
I am happy with the way pre-qualification program is conducted. No additional suggestions from me. The process of dossier
evaluation and the process of inspection are transparent and people from WHO are approachable.
Interpretation of regulatory guidlines should be clear.

should indicate inspection process earlier

Inconsitencies between Inspectors style and willingness to understand different interpretations of GMP and means of achieving
the same needs to be addressed

Survey: Comments in responses

z Providing clear explanations of GMP deficiencies observed
during inspection of a manufacturing site
Review of dossiers and subsequent responses should be addressed on fast
track
Inspection process is fair and up to the mark
Deficiencies must be evaluated with risk to the product, patient and process

z Providing clear interpretation of GMP requirements, resolving

issues and clarity of questions
Satisfied. Transparent
If response is not clear on site (following inspectors questions) - then should
say so on site and provide some suggestions
Inspectors inconsistent in willingness to understand different interpretations
of GMP s

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Dr AJ van Zyl | April 2011

Survey: Comments in responses

7.0
6.3*
6.0

Average Rating

5.7
5.0

6.1*
5.6

6.3*
5.8

6.2
6.0
5.5*
5.1*

5.0*
4.7*

4.7*
4.3
4.2

4.0

3.0

2.0

1.0

Providing clear
interpretation of GMP
requirements

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Dr AJ van Zyl | April 2011

Providing an efficient Providing an inspection The clarity of questions

asked during the
process that makes
process to resolve
inspection process
efficient use of
issues and questions
manufacturers time
raised following the
inspection of
manufacturing sites

Including inspectors
from your country or
region on the
inspection team

Survey: Comments in responses

50%

40%

30%

20%

10%

0%
1

Less Stringent --- More Stringent

WHO GMP vs US CFR and EU GMP: Interclarity Research & Consulting, Inc.

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Dr AJ van Zyl | April 2011

When asked how strongly they agree or disagree with the statement "WHO GMP requirements are more
stringent than EU or US FDA GMP requirements", the majority of manufacturers indicated that they were more
stringent.
Comment
It is quite descriptive and elaborative. Interpretation of WHO guidelines are very easy compared to others.Even minute
points covered in WHO GMP.
The sampling plan and protocols should be made more strict.
Such as provisions about sampling and the approval of changes etc.
WHO is specififying, how to perform the activities alongwith scientific rationale and explanations.
The inspection takes a long time, it covers a wide range of areas
The requirement of EU / MHRA is more as compared to WHO, it need to be harmonise
Sometimes they ask us to perform certain studies thrice which are not required by any other regulatory bodies
Regarding the aspects of safety and effectiveness
very specific like one batch vs 3 batch requirement for filling
eg. conducting all ID tests on each container even if a robust ID test is available for each container.
The guidance are more detailed, specific and useful such as Guidance on HVAC & Water System
All are respected.
Again this is a general comment where the guideline points are interpreted differently and understanding of the
inspectors whrere guideline are general.
Each and every points of the WHO guideline are covered while the inspection & suggesions were provided with
observations for compliance & suffieicnet time is give implementaion of corrective actions. All supporting documents were
also required for compliance to closure of audit.
accelerated Stability data requirement is 6months in case of WHO and where as 3months with USFDA.
Validation
data of three batches is a part of PQF. where as one batch and a commitment in USFDA.
The way WHO regulations are laid out and implemented, takes into account best of both EU and US FDA GMP
requirements. It covers overall GMP, products and processes.
The WHO requires 100% sampling from each container of a raw materia's lot when received for manufacturing a
formulation even if the vendor is validated.
It focuses more on the operational levels, not just paper work or procedures evidence. It also emphysizes detailed
practice and skills/capbility of employees.

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Dr AJ van Zyl | April 2011

Comments (WHO GMP more stringent)

z

Quite descriptive and elaborate. Interpretation of WHO GMP is very easy compared to others. Even minute points are
covered in WHO GMP

Guidances are more detailed, specific and useful such as HVAC and Water

WHO guidelines take into account the best of EU and FDA. It covers overall GMP, products and processes

WHO explains how to perform activities alongside with scientific rationale and explanations

Sampling
The sampling plan and protocols should be made more strict
Provisions about sampling and the approval of changes
WHO requires 100% sampling from each container even if the vendor is validated
Asking all ID tests on each container even if a robust ID test is available

Inspections take a long time and cover a wide range of areas

It focuses more on operational levels not just paper work or procedure evidence

The requirement of EU / MHRA is more compared to WHO - need to harmonize

They ask us to perform some studies thrice while others don't

Very specific like asking 3 batches for filing

Regarding safety and effectiveness

Accelerated stability data required for 6 months where FDA requests 3 months. Validation of three batches opposed
to one batch data (FDA)

Guidelines are general and different interpretations by inspectors

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Dr AJ van Zyl | April 2011

The way forward

z Invite comments from the floor
z Discussion
z List recommendations

z WHO Procedure:
z Secretariat will take it to the Expert Committee
z Discussion, recommendation: Action if needed
z Revision, comment, informal consultation, Expert Committee
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Dr AJ van Zyl | April 2011